The broad objective of this research plan is to gain knowledge of the fundamental cellular and biochemical mechanisms underlying long-term potentiation (LTP) of brain excitatory synaptic transmission. LTP is a form of neural activity-dependent synaptic enhancement that has become a leading model for a cellular mechanism of memory storage in the mammalian central nervous system (CNS). LTP is induced by processes residing in the postsynaptic side of synapses, and expressed, at least in part, by changes in the presynaptic terminal. Evidence has mounted that a signal, the so- called retrograde messenger, passes from the postsynaptic to the presynaptic side of the synapse to induce LTP. The identity of this messenger is controversial, but the leading candidate is nitric oxide (NO). This study will focus on the role of NO and other potential diffusible retrograde messengers in producing LTP, using the rat hippocampal slice as the experimental system. Experiments will be conducted using a range of electrophysiological techniques. Specifically, we aim to elucidate three aspects of diffusible messenger function in LTP. First, we will study the processes that are activated by NO, with a particular emphasis on determining if these reside in the presynaptic terminal. Second, we will study the process that can communicate LTP from stimulated synapses to non-stimulated synapses. This co-called distributed potentiation appears to rely on a diffusible messenger and depends on NO. Finally, we will compare NO and non-NO- dependent forms of lTP in the CA1 region of the hippocampus as a way of determining the unique role that NO plays in LTP.